novavax nanoflu vaccine induced improved immune...

© 2018 Novavax, Inc. All rights reserved. NASDAQ:NVAX

April 4, 2018

Novavax NanoFlu vaccine induced improved immune responses against homologous and drifted A(H3N2) viruses in older adults compared to egg-based, high-dose, influenza vaccineWorld Vaccine Congress

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Outline

The need for an improved flu vaccine

The nanoparticle vaccine and Matrix-M adjuvant

Broadly cross-reactive A(H3N2) immune responses in ferrets

Phase 1/2 trial design

Phase 1/2 data

Conclusions

Two critical problems undermine seasonal influenza VE:1) Classical antigenic drift (long-standing):

• Exemplified by poor VE during 2014-15 US flu season2 (emergence of A/Switzerland H3N2)

2) Egg-adaptive antigenic changes (recently recognized):• Exemplified by poor A(H3N2) VE during 2017-18 US flu season in spite of an apparent “match”3

• Existence of well-characterized egg-adaptive mutations in HA antigenic epitopes (T160K)4

• Problematic given that 87% of flu vaccines deployed in the US are produced in eggs5

Compounding effect of both problems likely contributed to recent poor A(H3N2) VE noted during the 2017 influenza season in Australia

• A level of drift likely present with the emergence of A/Singapore-NFIMH (H3N2)-like viruses, though not rising to the strict definition of “drift” by WHO6

• A significant concomitant impact of egg-adaptive antigenic changes was observed

CAN WE DO BETTER?Broader protection? Eliminate egg-adaptive changes?

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Why do we need a better seasonal influenza vaccine?

Consistently suboptimal seasonal influenza vaccine effectiveness (VE) in recent years1, notably in the context of:

A(H3N2) Older adultsviruses

1. Russell Vaccine 2018.2. MMWR June 20153. MMWR Feb 20184. Zost PNAS 20175. CDC Influenza Grand Rounds Jan 20186. VRBPAC Feb 2018

Playing catch-up and does “one strain fit all”? Rapid evolution and diversity of A(H3N2) viruses

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Adapted from CDC Grand Rounds. January 18, 2018. https://www.cdc.gov/cdcgrandrounds/archives/2018/January2018.htm

4 CDC collaboration with NextFlu. Neher, Bedford etal.

Most common in Australia summer ‘17

2009 2010 2011 2012 2013 2014 2015 2016 2017

Epitope Changes

1 15Number of significant changes to important

regions of the hemagglutinin gene

= Vaccine Viruses

A/Singapore

A/Hong Kong

A/Switzerland

A/TexasA/Victoria

A/Perth

Most common in U.S. 17/18 season


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5 CDC collaboration with NextFlu. Neher, Bedford etal.


2009 2010 2011 2012 2013 2014 2015 2016 2017

Epitope Changes



= Vaccine Viruses

A/Singapore

A/Hong Kong

A/Switzerland

A/TexasA/Victoria

A/Perth


Circulating H3N2 viruses present in 2017-18 Season

The nanoparticle influenza vaccine and Matrix-M adjuvant

• Recombinant hemagglutinin (HA) nanoparticle vaccine• Baculovirus/Sf9 insect cell system• Express recombinant, full-length, wild-type HA that assembles into HA homotrimers• Purified HA homotrimers form higher order nanoparticle structures of 20-40 nm • 2 to 9 HA homotrimers per nanoparticle held together by hydrophobic interactions• Rapid, high-yield, high purity, production process

• Potent saponin-based Matrix-M adjuvant• Extracted from bark of Quillaja saponaria Molina• Enhancement of activated T cell, B cell, and APC

populations• Induction of functional, and broadly cross-reactive

antibodies• Induction of polyfunctional T cells, both CD4+ and CD8+• Antigen sparing in the context of pandemic influenza

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In ferrets, tNIV induced broadly cross-neutralizing immune responses to drifted A(H3N2) viruses

4096

1024

256

64

16

4

50%

MN

Tite

rs (L

og2)

NIV + Matrix MFluzone HDFluzone QIV

Novel hemagglutinin nanoparticle influenza vaccine with Matrix-M™ adjuvant induces hemagglutination inhibition, neutralizing, and protective responses in ferrets against homologous and drifted A (H3N2) subtypes

G Smith, Y Liu, et al.Vaccine 35 (2017) 5366-5372

• Conducted in U.S.1 across 3 sites in North Carolina• 330 clinically-stable adults ages ≥60 years• Randomized 1:1:1, stratified by age (60-74, and 75+)• Single IM dose on day 0 of:

• tNIV: 15µg each HA (45µg total) + 50µg Matrix-M, or• tNIV: 60µg each HA (180µg total) + 50µg Matrix-M, or• Licensed egg-based high-dose (180µg total), trivalent, inactivated influenza vaccine (IIV3-HD)(Fluzone-HD)

• Day 21 rescue dose of IIV3-HD or placebo• All 3 vaccines included 2017-18 WHO recommended NH strains:

• A/Michigan (H1N1); A/Hong Kong (H3N2); B/Brisbane

• Objectives• Safety: assessed through Day 21• Immunogenicity: HAI and MN against vaccine-homologous and drifted H3N2 strains through Day 21

Phase 1/2 trial design

1. Clinicaltrials.gov NCT#03293498

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N 109 111 110Mean age (SD) 69 (6.3) 68 (6.2) 69 (6.1)

Median age 68 67 69

Count (%) ≥65 y.o. 73 (66.9) 76 (68.4) 79 (71.8)

Count (%) ≥75 y.o. 19 (17.4) 20 (18.0) 20 (18.2)

%M / % F 46.8/53.2 45.9/54.1 48.2/51.8

Race/Ethnicity

White (%) 83.5 88.3 90.0

Black/African American (%) 15.6 11.7 8.2

All other (%) 0.9 0 0.9

Self-identified as Hispanic (%) 0.9 0.9 0.9

Flu vaccine in 2016-17 (%) 95 (87.2) 94 (84.7) 93 (84.5)

Any flu vaccine w/i 3 yrs (%) 102 (93.6) 101 (91.0) 102 (92.7)

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Demographic data

45µg tNIV HA + MxM 180µg tNIV HA + MxM IIV3-HD (Fluzone HD)Variable

N 109 111 110Counts (%) of Subjects with Events

Any treatment emergent adverse event (TEAE)

40 (37%) 52 (47%) 51 (46%)

Any Solicited TEAE 30 (28%) 37 (33%) 38 (35%)

Local solicited 15 (14%) 26 (23%) 30 (27%)

Severe local solicited 2 (2%) 0 (0%) 1 (1%)

Systemic Solicited 23 (21%) 24 (22%) 20 (18%)

Severe systemic solicited 2 (2%) 4 (4%) 0 (0%)

Unsolicited TEAE 22 (20%) 24 (22%) 20 (18%)

Severe unsolicited 0 (0%) 2 (2%) 1 (1%)

Severe & related unsolicited 0 (0%) 0 (0%) 1 (1%)

Medically-attended unsolicited 9 (8%) 6 (5%) 2 (2%)

Serious adverse events (SAEs) 0 (0%) 1 (1%) 0 (0%)

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Top-line safety data

45µg tNIV HA + MxM 180µg tNIV HA + MxM IIV3-HD (Fluzone HD)Safety events (thru 21 days)

61.0

127.0

58.0

159.0

62.0

116.0

69.0

146.0

66.0

210.0

65.0

171.0

58.0

87.0

55.0

106.0

54.0

109.0

0

50

100

150

200

250

Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21

HAI antibody responses (GMTs) against wild-type vaccine-homologous strains (2017-18)

Geo

met

ric M

ean

Tite

r (G

MT)

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45µg NanoFlu 180µg NanoFlu IIV3-HD 45µg NanoFlu 180µg NanoFlu IIV3-HD 45µg NanoFlu 180µg NanoFlu IIV3-HDA/HongKong H3N2 A/Michigan H1N1 B/Brisbane

HAI antibody response (GMFRs) against wild-type vaccine-homologous strains (2017-18)

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2.1

2.7

1.92.1

3.2

2.6

1.5

1.92.0

0

1

2

3

4

45µg NanoFlu 180µgNanoFlu

IIV3‐HD 45µg NanoFlu 180µgNanoFlu


IIV3‐HD

A/HongKong H3N2 A/Michigan H1N1 B/Brisbane

Geo

metric

Mean Fold Tite

r Rise (95%

CI)

Ratio of Day 21 GMTs47% ↑ p=0.0056

2.3

3.4

2.3 2.2

3

2.22.5

3.9

2.5

2.1

2.7

1.92.2

3.1

1.9

0

1

2

3

4

5

HAI antibody responses (GMFRs) against 5 generations of drifted wild-type A(H3N2) strains






Geo

met

ric M

ean

Fold

Tite

r Ris

e (9

5% C

I)

13

45µg NanoFlu

180µg NanoFlu

IIV3-HD 45µg NanoFlu

180µg NanoFlu


180µg NanoFlu


180µg NanoFlu


180µg NanoFlu

IIV3-HD

A/Victoria H3N2 A/Texas H3N2 A/Switzerland H3N2 A/Hong Kong H3N2 A/Singapore H3N2

2.3

3.4

2.3 2.2

3

2.22.5

3.9

2.5

2.1

2.7

1.92.2

3.1

1.9

0

1

2

3

4

5

HAI antibody responses (GMFRs) against 5 generations of drifted wild-type A(H3N2) strains






Geo

met

ric M

ean

Fold

Tite

r Ris

e (9

5% C

I)

14

45µg NanoFlu

180µg NanoFlu


180µg NanoFlu


180µg NanoFlu


180µg NanoFlu


180µg NanoFlu

IIV3-HD

A/Victoria H3N2 A/Texas H3N2 A/Switzerland H3N2 A/Hong Kong H3N2 A/Singapore H3N2

A(H3N2) viruses currently circulating in North America

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Neutralization antibody responses (GMTs) against wild-type vaccine-homologous strains (2017-18)

913

1,712

764

1,665

900

2,079

253

1,011

213

1,541

210

1,045

90 144 91 18177

213

0

500

1000

1500

2000

2500

3000

Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21 Day 0 Day 21

45µg NanoFlu 180µg NanoFlu IIV3-HD 45µg NanoFlu 180µg NanoFlu IIV3-HD 45µg NanoFlu 180µg NanoFlu IIV3-HD


Neutralization antibody responses (GMFRs) against wild-type vaccine-homologous strains (2017-18)

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1.9 2.2 2.3

4.0

7.2

5.0

1.6 2.02.8

0.0

2.0

4.0

6.0

8.0

10.0

12.0




IIV3‐HD


Geo

metric

Mean Fold Tite

r Rise (95%

CI)

Neutralization antibody responses (GMFRs) against circulating wild-type H3N2 strains

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2.1

2.82.5

1.92.2

2.3

2.8

3.5

2.1

0.0

1.0

2.0

3.0

4.0

5.0




IIV3‐HD

A/Switzerland H3N2 A/Hong Kong H3N2 A/Singapore‐NFIMH H3N2

Geo

metric

Mean Fold Tite

r Rise (95%

CI)

Vaccine Strain 2015-16Historic Drift Vaccine Strain 2016-17 and 17-18 Vaccine Strain 2018-19

Forward Drift


Neutralization antibody responses (GMFRs) against egg-adapted vs. wild-type A/Singapore H3N2 viruses


3.8 3.93.5

2.1

0.0

1.0

2.0

3.0

4.0

5.0

180µg NanoFlu IIV3‐HD 180µg NanoFlu IIV3‐HD

A/Singapore H3N2 (egg‐adapted) A/Singapore H3N2 (wild‐type)

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Geo

met

ric M

ean

Fold

Tite

r Ris

e (9

5% C

I) Ratio of Day 21 GMTs61% ↑ p=0.0002

Nanoflu induced improved neutralization antibody responses (GMFRs) against wild-type vs. egg-adapted A/Singapore H3N2 viruses underscoring the problem of egg-adaptive mutations

Neutralization antibody responses against wild-type circulating viruses are the most clinically relevant

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• Avoidance of egg-adaptive antigenic changes leads to substantial improvements in vaccine-homologous A(H3N2) HAI antibody responses

• Induction of immune responses against conserved HA head based epitopes expands cross-reactive HAI responses against a broad panel of A(H3N2) drift variants:

• 28-38% increase in HAI against distant historic drifted viruses (2012-13, 2014-15) • 54% increase in HAI against recent historic drifted viruses• 64% increase in HAI against forward drifted virus, A/Singapore

• Most substantial HAI antibody increases were observed against a “forward” drifted A(H3N2) virus, A/Singapore, offering a potential safeguard against the age-old problem of classical antigenic drift

• Broad cross-reactivity to antigenically diverse co-circulating A(H3N2) viruses ensures that “one size fits all” regardless of geography

• Next steps• Phase 2 in Fall 2018: quadrivalent formulation• Phase 3 anticipated in 2H 2019

Discussion


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20 CDC collaboration with NextFlu. Neher, Bedford et al.


2009 2010 2011 2012 2013 2014 2015 2016 2017

Epitope Changes



= Vaccine Viruses

A/Singapore

A/Hong Kong

A/Switzerland

A/TexasA/Victoria

A/Perth


Circulating H3N2 viruses present in 2017-18 Season

Playing catch-up and does “one strain fit all”? Nanoflu has the potential to provider broader protection

21



Most common in U.S. this season

2009 2010 2011 2012 2013 2014 2015 2016 2017

Epitope Changes



= Vaccine Viruses

A/Singapore

A/Hong Kong

A/Switzerland

A/TexasA/Victoria

A/Perth

NanoFlu vaccine has potential to provide broader protection against antigenic drift

Circulating H3N2 viruses present in 2017-18 season

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novavax nanoflu vaccine induced improved immune...

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